1-halo-2-hydroxy-3-(protected)amino-4-substituted butanes represented by the following general formula:
wherein X is a halogen, R is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, and substituted aryl, and R1 represents an amino-protecting group are useful in producing 1,2-epoxy-3-(protected)amino-4-substituted butane derivatives represented by the following general formula:
wherein R and R1 are as defined above. The 1-halo-2-hydroxy-3-(protected)amino-4-substituted butanes of formula 1 can be prepared by microbiologically reducing a (3S)-1-halo-2-oxo-3-(protected)amino-4-substituted butane substrate having the following general formula:
wherein X, R, and R1 are as defined above.
The 1,2-epoxy-3-(protected)amino-4-substituted butane derivatives of formula (2) may be used to produce various HIV protease, ACE, and renin inhibitors. The various HIV protease inhibitors that may be produced with the formula (2) intermediate include but are not limited to, for example, the HIV protease inhibitors disclosed in U.S. Pat. No. 5,849,911 at column 2, line 13 to column 12, line 59, wherein said disclosure is hereby incorporated herein by reference. The typical HIV protease inhibitor that may be produced with the formula (2) intermediate includes but is not limited to, for example, the [3S-(3R*,8R*,9R*,12R*)]-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6{[4-(2-pyridinyl)phenyl]methyl}-2,3,6,10,13-pentaazaretetradecanedioic acid dimethyl ester compound disclosed in U.S. Pat. No. 5,849,911.
The 1,2-epoxy-3-(protected)amino-4-substituted butane derivatives of formula (2) can be synthesized in accordance with, for example, the following reaction scheme (1):
wherein X, R and R1 of each of the Formulas 4-8 are as defined above. In accordance with reaction scheme (1), microbially reducing the formula 3 substrate to desired (2R,3S)-1-halo-2-hydroxy-3-(protected)amino-4-substituted butane diastereomer of formula 4 can also result in the production of undesired (2S,3S)-1-halo-2-hydroxy-3-(protected)amino-4-substituted butane diastereomer by-product of formula 5 and undesired des-halo alcohol (3S)-2-hydroxy-3-(protected)amino-4-substituted butane impurity of formula 8. The desired (2R,3S)-1-halo-2-hydroxy-3-(protected)amino-4-substituted butane diastereomer of formula 4 is subsequently treated with base and epoxidized to desired (2R,3S)-1,2-epoxy-3-(protected)amino-4-substituted butane of formula 6. The undesired (2S,3S)-1-halo-2-hydroxy-3-(protected)amino-4-substituted butane diastereomer by-product of formula 5, however, is upon being treated with base epoxidized to undesired (2S,3S)-1,2-epoxy-3-(protected)amino-4-substituted butane of formula 7.